Benzodiazepine derivatives

ABSTRACT

Thieno[1,5]benzodiazepines having useful CNS activity containing the novel tricyclic ring system: ##STR1## the 10-position being substituted by an amino, preferably a piperazino, group.

This is a continuation of Ser. No. 633,895 filed Nov. 20, 1975 nowabandoned.

This invention relates to a novel class of compounds having usefulcentral nervous system (hereinafter abbreviated to `CNS`) activityand/or which are useful as intermediates in preparing such activecompounds. The invention also includes processes for preparing the novelcompounds of the invention. Furthermore, the invention includes withinits scope pharmaceutical compositions containing the active compoundsand methods of treating animals, including humans, comprisingadministering thereto an effective dose of the compound or compounds orof pharmaceutical compositions comprising the active compound orcompounds. More particularly, the invention is concerned with thehitherto unknown thieno[1,5]benzodiazepine ring system depicted below:##STR2## where the symbol: ##STR3## signifies a thiophene ring.

In recent times, there has been intense activity in the area ofpharmaceutical chemistry relating to tricyclic and benzodiazepinesystems. A large number of patents have issued of which United KingdomPat. Nos. 980,853; 1,291,684; 1,380,242; 1,380,243; 1,380,244 and UnitedStates Patents Nos. 2,893,992; 3,102,116; 3,109,843; 3,136,815;3,474,099; 3,654,286; 3,749,786 and 3,842,082 represent only a verysmall proportion.

According to the present invention there is provided a novelthieno[1,5]benzodiazepine of formula (I): ##STR4## or an acid additionsalt thereof, wherein R¹ and R² independently represent hydrogen, C₁₋₄alkyl, C₂₋₄ alkenyl, C₃₋₆ cycloalkyl, halogen, C₁₋₄ haloalkyl, nitro,amino, C₂₋₄ acylamino, hydroxyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio or a groupof formula --SO₂ N(R⁴)₂ or SO₂ R⁴, where R⁴ is C₁₋₄ alkyl; where

(A) R⁵ is a group of formula: ##STR5## wherein R⁶ is hydrogen, phenyloptionally substituted by halogen or C₁₋₄ haloalkyl, C₁₋₄ alkyl, C₃₋₆cycloalkyl, C₂₋₄ alkenyl, C₁₋₄ alkanoyl, benzyl, C₁₋₄ carbalkoxy or--(CH₂)_(n) OX, where n is 2 or 3 and where X is hydrogen or an esterradical; or

(B) R⁵ is a group of formula:

    --NH-(CH.sub.2).sub.n -Z

where n is 2 or 3 and Z is ##STR6## where R⁶ is as above defined.##STR7## where R" and R'" are independently hydrogen or C₁₋₄ alkyl, or

(v) OH and wherein the group ##STR8## represents an optionallysubstituted thiophene ring fused to the diazepine nucleus.

Preferably, in the compounds of formula (I) and their acid additionsalts, R¹ and R² independently represent hydrogen, C₁₋₄ alkyl, halogen,C₁₋₄ haloalkyl, nitro, amino, C₁₋₄ alkoxy, C₁₋₄ alkylthio or a group offormula -SO₂ N(R⁴)₂ where R⁴ is C₁₋₄ akyl; and

(A) R⁵ is a group of formula: ##STR9## wherein R⁶ is hydrogen, phenyloptionally substituted by halogen, C₁₋₄ alkyl, C₁₋₄ carbalkoxy or-(CH₂)_(n) OH where n is 2 or 3; or (B) R⁵ is a group of formula:

    -NH-(CH.sub.2).sub.n -Z

where n is 2 or 3 and Z is ##STR10##

where R⁶ is as above defined immediately above, ##STR11##

where R" and R'" are independently hydrogen or C₁₋₄ alkyl. Those skilledin the art will appreciate that the novel thieno[1,5]benzodiazepines ofthe invention can exist in three forms which can be represented by thefollowing structures: ##STR12##

In the above structural formulae, for ease of representation, thethiophene ring is shown as unsubstituted but it is to be understood thatthe thiophene ring may be substituted, for instance, by one or twogroups selected from C₁₋₈ alkyl, typically C₁₋₆ alkyl, C₂₋₄ alkenyl,C₁₋₄ haloalkyl, C₂₋₄ alkanoyl, nitro, halogen and optionally substitutedphenyl. In addition, in the structures of formulae (II) and (IV), thethiophene ring may be fused to a C₃₋₈ cycloalkyl ring.

Preferred compounds falling within the scope of compounds defined in anyof formulae (I) to (IV) above are those having one or more of thefollowing characteristics:

(A) R¹ is a 6 or 7-halo substituent, such as chlorine or fluorine;

(B) R¹ is a 7-halo substituent such as chlorine or fluorine when R² ishydrogen;

(C) R¹ is a 7-fluoro substituent when R² is hydrogen

(D) R² is hydrogen;

(E) R¹ or R² is trifluoromethyl;

(F) R¹ is a 6- or 7-trifluoromethyl substituent when R² is hydrogen;

(G) R¹ or R² is methylthio or methoxy;

(H) R¹ and R² both represent halogen atoms, for example fluorine;

(I) R⁵ is a group of formula: ##STR13##

where R⁶ is hydrogen, C₁₋₄ alkyl, benzyl, or (CH₂)_(n) OX;

(j) r⁵ is a group of formula: ##STR14## (K) the compound of formula (I)has the structure (II); (L) the thiophene ring is substituted by a C₁₋₄alkyl group, such as ethyl;

(M) the thiophene ring is unsubstituted;

(N) the thiophene ring is substituted by an electron withdrawing groupsuch as halogen, nitro, trifluoromethyl or C₂₋₄ alkanoyl.

A presently most preferred class of compounds is that having features

(A) to (E), (J) and (L).

One particularly active compound falling within this class which may bementioned is2-ethyl-7-fluoro-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine,both in the form of its free base and pharmaceutically acceptable saltsthereof.

The term "C₁₋₄ alkyl" as used herein means a straight or branched chainalkyl group containing from 1 to 4 carbon atoms, i.e. methyl, ethyl,isopropyl, n-butyl, s-butyl, isobutyl, and n-butyl. The term "C₁₋₄haloalkyl" means the aforesaid alkyl groups substituted by one or morehalogen atoms, e.g. trifluoromethyl. The terms "C₁₋₄ alkoxy" and "C₁₋₄alkylthio" refer to the aforementioned alkyl groups attached through anoxygen or sulphur atom respectively to the benzene or thiophene ring.

The term "C₂₋₄ alkenyl" refers to groups such as vinyl, allyl andbutenyl.

The term "amino" as used herein indicates a group of formula -NH₂ andalso substituted amino groups such as mono-C₁₋₄ alkylamino and di-C₁₋₄alkylamino groups. The term C₂₋₄ acylamino means an amino groupsubstituted by a C₂₋₄ acyl group such as acetyl. The term "C₁₋₄alkanoyl" refers to groups such as formyl or acetyl.

"C₃₋₈ cycloalkyl" means a saturated ring having from 3 to 8 carbon atomsin the ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, orcyclooctyl. The term "optionally substituted phenyl" as used hereinmeans a phenyl group unsubstituted or substituted by one or more groupssuch as halogen, trifluoromethyl, methyl, methoxy or nitro.

Examples which may be given of the compounds of the invention are:-

2-ethyl-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine7-chloro-2-ethyl-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

2-ethyl-7-fluoro-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

2-ethyl-7-trifluoromethyl-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

7-amino-2-ethyl-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

2-ethyl-7-nitro-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

2-ethyl-6-fluoro-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

2-methyl-7-N,N-dimethylsulphonamido-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

2-pentyl-7-fluoro-10-(4'-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

2-ethyl-6-methyl-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

2-methyl-7-methoxy-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

6,7-difluoro-2-ethyl-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

2-ethyl-7-methylthio-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

6,8-difluoro-2-ethyl-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]-benzodiazepine

7-fluoro-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

7-chloro-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

7-chloro-1-methyl-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

1,2-dimethyl-7-chloro-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

7-chloro-2-methyl-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

6-trifluoromethyl-2-ethyl-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

2-vinyl-7-fluoro-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

2-vinyl-7-trifluoromethyl-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

7-chloro-2-ethyl-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepine

2-ethyl-7-fluoro-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepine

2-ethyl-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepine

2-ethyl-7-trifluoromethyl-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepine

7-amino-2-ethyl-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepine

2-ethyl-7-nitro-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepine

2-ethyl-6-fluoro-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepine

2-methyl-7-N,N-dimethylsulphonamido-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepine

2-ethyl-6-methyl-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepine

2-methyl-7-methoxy-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepine

6,7-difluoro-2-ethyl-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepine

2-ethyl-7-methylthio-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepine

6,8-difluoro-2-ethyl-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepine

7-fluoro-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepine

7-chloro-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepine

2,3-dimethyl-7-chloro-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepine

7-chloro-2-methyl-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepine

9-fluoro-12-(4'-methyl-1'-piperazinyl)-6H-1,2,3,4-tetrahydrobenzo-[b]thieno[2,3-b][1,5]benzodiazepine

2-ethyl-7-fluoro-10-[4'-(2-hydroxyethyl)-1-piperazinyl]-4H-thieno[2,3-b][1,5]benzodiazepine

2-ethyl-7-fluoro-10-[4'-(3-hydroxypropyl)-1-piperazinyl]-4H-thieno[2,3-b][1,5]benzodiazepine

2-octyl-7-fluoro-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

2-ethyl-7-fluoro-10-(1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

2-ethyl-7-fluoro-10-[N-(N',N'-dimethylaminoethyl)amino]-4H-thieno[2,3-b][1,5]benzodiazepine

2-ethyl-7-fluoro-10-(2'-N-piperidinoethyl)amino-4H-thieno[2,3-b][1,5]benzodiazepine

2-ethyl-7-fluoro-10-(4'-allyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

2-ethyl-7-chloro-10-[3'-(4-phenyl-1-piperazinyl)propyl]amino-4H-thieno[2,3-b][1,5]benzodiazepine

2-ethyl-7-chloro-10-[3'-(4-hydroxyethyl-1-piperazinyl)propyl]-amino-4H-thieno[2,3-b][1,5]benzodiazepine

3-methyl-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

3-methyl-7-chloro-10-(4'-methyl-1'-methyl-1'-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

7-fluoro-10-(4'-acetyl-1'-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

7-trifluoromethyl-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

7-amino-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

7-acetylamino-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

7-methylamino-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

7-dimethylamino-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

7-nitro-10-(4'-methyl-1'-piperzinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

6-fluoro-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

3-methyl-7-N,N-dimethylsulphonamido-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepine

2-ethyl-7-hydroxy-10-(4'-methyl-1'-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

6-methyl-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

3-methyl-7-methoxy-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

6,7-difluoro-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

7-methylthio-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

6,8-difluoro-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

7-chloro-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

7-fluoro-10-(4'-methyl-1'-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

2-ethyl-7-fluoro-10-[4'-(2-hydroxyethyl)-1'-piperazinyl]-4H-thieno[3,2-b][1,5]benzodiazepine

As indicated above, the novel thieno[1,5]benzodiazepines of theinvention are useful both in their free base and acid addition saltforms. The acid addition salts are preferably the pharmaceuticallyacceptable, non-toxic addition salts with suitable acids, such as thosewith inorganic acids, for example hydrochloric, hydrobromic, nitric,sulphuric or phosphoric acids, or with organic acids, such as organiccarboxylic acids, for example, glycollic, maleic, hydroxymaleic,fumaric, malic, tartaric, citric, salicyclic, o-acetoxybenzoic,nicotinic or isonicotinic acid, or organic sulphonic acids for examplemethane sulphonic, ethane sulphonic, 2-hydroxyethane sulphonic,toluene-p-sulphonic, or naphthalene-2-sulphonic acid. Apart frompharmaceutically acceptable acid addition salts, other salts are alsoincluded within the scope of acid addition salts such as, for example,those with picric or oxalic acid; they may serve as intermediates in thepurification of the compounds or in the preparation of other, forexample, pharmaceutically acceptable, acid addition salts, or are usefulfor identification, characterization or purification of the bases.

According to a second aspect of the invention there is provided a methodof preparing a compound of formula (I) which comprises:

(a) reacting an amine of formula R⁵ H with a compound of formula (V):##STR15## where R¹, R² and R⁵ are as defined above and wherein ##STR16##represents an optionally substituted fused thiophene ring as before, andwherein Q represents a radical capable of being split off with thehydrogen atom of the amine R⁵ H, followed, if desired, in the case whereR⁵ is ##STR17## and R⁶ is C₁₋₄ carbalkoxy by hydrolysis to the amine inwhich R⁶ is hydrogen; or

(b) reacting a compound of formula (VI): ##STR18## with an alkylatingagent of formula R⁶ X, where R⁶ is as above defined with the exceptionof hydrogen and phenyl, and where X is a reactive atom.

It should be noted that both processes (a) and (b) above are "analogyprocesses" of a reaction type previously described in the literature(see, for example, United Kingdom Patent Specification No. 1,216,523 forthe reaction (a) and almost any standard treatise in the art forreferences to alkylation). Thus, once the nature of the startingmaterials and final products is understood, those skilled in the artwill appreciate the identity of suitable Q and X radicals, as well asappropriate reaction conditions.

However, it may be mentioned that the radical Q may be hydroxyl orthiol, an alkoxy or alkylthio group containing 1 to 4 carbon atoms, e.g.the methoxy or methylthio group, an aryloxy, aralkylthio or arylthiogroup which may be activated as a leaving group by substituents thereonconveniently in the aryl moiety thereof, e.g. the p-nitrobenzylthiogroup, an alkyl- or arylsulpheno group, preferably activated as aleaving group by substituents on the sulphur atom and the hydrocarbonmoiety thereof, e.g. a tosyl group, a halogen atom, conveniently achlorine atom, an amino group or a mono- or dialkyl-substituted aminogroup, the or each alkyl substituent thereof containing 1 to 4 carbonatoms.

Preferably, Q is hydroxyl, thiol, C₁₋₄ alkoxy, C₁₋₄ alkylthio, halogenor NH₂.

Most preferably, Q is hydroxyl or thiol, when the intermediates offormula (V) exist predominantly in their amide and thioamide forms:##STR19##

When Q is hydroxyl, and thus the compound of formula (V) is an amide,reaction (a) can be accomplished in the presence of titaniumtetrachloride. This last named reagent has the ability to react with theamine of formula R⁵ H to form a metal amine complex. Other metalchlorides such as those of zirconium, hafnium or vanadium also possessthis property. The reaction is preferably carried out in the presence ofan acid binding agent such as a tertiary amine, for example,triethylamine. Alternatively, the reaction can be carried out usingexcess of the amine of formula R⁵ H to act as acid-binding agent.

Any suitable organic solvent such as toluene or chlorobenzene can beused although it has been found that the use of anisole is particularlydesirable at least as a co-solvent, in view of its ability to form asoluble complex with TiCl₄.

If desired, elevated temperatures (up to 140° C.) can be used toexpedite the reaction. A preferred temperature range for carrying outthe reaction lies in the range 50° to 100° C.

The amidines of formula (V), i.e. where Q is NH₂, can be similarlycondensed with the amine of formula R⁵ H, although the yield from thisreaction may be rather low. In fact, it is generally preferable toconvert the amidine into the corresponding amide by alkaline hydrolysisand use the thus formed amide for the condensation reaction.

Thioamides of formula (V), Q is SH, can be prepared by treating asolution of the corresponding amide in an anhydrous basic solvent suchas dry pyridine, with phosphorous pentasulphide. Similarly, the amidesmay be converted to iminothioethers, iminoethers or iminohalides, orother derivatives containing active Q radicals as specified above, bytreatment with conventional reagents such as, for an iminochloride,phosphorous pentachloride. Such derivatives derived from the amides tendto be more reactive towards the amine R⁵ H and can usually be reactedwith that entity without the necessity for the presence of TiCl₄.

Compounds of formula (VI) can be alkylated by dissolving the amine in asuitable inert polar solvent such as ethanol, adding the alkylatingagent to the solution thus formed and refluxing in the presence of base.X can be any suitable reactive atom such as chlorine, bromine or iodineor a reactive group such as tosyl or mesyl.

Compounds of formula (I) in which R⁵ represents: ##STR20## arepreferably prepared by hydrolysis of the corresponding C₁₋₄ carbalkoxyderivative.

Electrophilic substitution reactions on the aromatic nucleus can, ifdesired, be carried out on compounds of formula (I) or (V) inconventional manner to produce derivatives bearing electron-withdrawinggroups on the thiophene ring. For instance, acetylation of an amide offormula (V) can be effected using acetyl chloride/SnCl₄. This amide mayalso be halogenated using, for example, N-chlorosuccinimide to give thecorresponding chlorinated derivative. Products of formula (I) in whichR¹ or R² are NH₂ may be acylated or alkylated in conventional manner toform the corresponding N-acyl and N-alkylamino derivatives.N-Hydroxyalkylpiperazines, i.e.R⁶ is --(CH₂)_(n) OH, can be esterifiedusing acid chlorides of fatty acids to give corresponding esters, suchas decanoates or enanthates.

The compounds of formula (I) produced by the foregoing process may beisolated per se or may be converted to their corresponding acid additionsalts using conventional methods.

The amides of formula (V) can be formed by a novel process whichinvolves the intramolecular ring-closure of an amino ester of formula(VII): ##STR21## where R⁹ is C₁₋₄ alkyl, e.g. ethyl, and R¹, R² and##STR22## are as defined previously. This reaction can be accomplishedusing dimsyl sodium in a suitable solvent, preferably dimethylsulphoxide.

Alternatively, amides of formula (V) can be produced by intramolecularring-closure of an amino acid of formula (VIII): ##STR23## usingdicyclohexylcarbodiimide (D.C.C.) with a suitable solvent such astetrahydrofuran. The amino acids can be obtained from the esters bybasic hydrolysis using, e.g. NaOH/EtOH.

As mentioned previously, a convenient way of preparing amides of formula(V) involves the following reaction: ##STR24## The hydrolysis may becarried out using alkaline hydrolytic conditions, for example, K₂ CO₃/H₂ O/EtOH.

One convenient method of preparing amidines of formula (IX) isillustrated below: ##STR25## Alternatively, amidines in the[3,4-b]system may be prepared by the following reaction sequence:##STR26## where X¹ and X² indicate optional substituents on thethiophene ring. As can be seen, the above reaction involves an"aromatisation" reaction using chloranil and xylene.

Alternatively, the above condensation reaction may be effected usingo-phenylenediamines in place of the nitroanilines.

The esters of formula (VII) are novel compounds which can be prepared bycondensation of a thiophene compound of formula: ##STR27## where R⁹ isas above defined, with an ortho-fluoro-nitrobenzene of formula:##STR28## in the presence of an n-butyl lithium derivative, or in thepresence of a base such as sodium hydride, sodium amide, triethylamine,or K₂ CO₃ in dimethyl sulphoxide, to form a nitro ester of formula:##STR29## which can then be reduced to the amino ester of formula (VII)catalytically, for instance using hydrogen over palladium on charcoal,or chemically using Zn/NH₄ Cl, ammonium polysulphide or Fe/HCl. Forexample, 4H-thieno[2,3-b][1,5]benzodiazepin-10-ones can be prepared bythe following illustrative reaction scheme: ##STR30##

Other thieno[1,5]benzodiazepin-10-ones can be similarly prepared via theamino ester route outlined above.

The thiophene starting materials used in the processes of the inventionare either known compounds, see, for example, Chem. Berichte, 99,94-100, (1966) J. Am. Chem. Soc., 68 2232 (1946) and Dutch PatentApplication No. 66 04742, or can be prepared by conventional techniquesfrom known compounds. The o-fluoro nitrobenzene intermediates are eithercommercially available or can be simply prepared from commerciallyavailable substances.

It will be understood the scope of the invention extends not only to anoverall process for preparing the novel compounds of the invention asdescribed hereinbefore but also to the individual synthetic steps asherein described, and combinations of two or more of such syntheticsteps. Further, the intermediates of formula (V), (VII), (VIII), (IX)and (X) are all novel compounds and are provided in further aspects ofthe invention.

As stated previously, the compounds of the invention have useful centralnervous system activity. This activity has been demonstrated inextensive testing in animal models using well-established procedures,such as the production of catalepsy, block of conditioned avoidanceresponse and reversal of amphetamine-induced stereotyped behaviour inrats. Specifically, the compounds of formula (I) and acid addition saltsthereof, are potent centrally acting compounds with neuroleptic,sedative or relaxant or anti-emetic properties. These properties,coupled with their high therapeutic index, render them useful in thetreatment of mild anxiety states and certain kinds of psychoticconditions such as schizophrenia and acute mania.

The compounds of this invention are effective over a wide dosage range,the actual dose administered being dependent on such factors as theparticular compound being used, the condition being treated and the typeand size of mammal being treated. However, the dosage required willnormally fall within the range of 0.1 to 20 mg./Kg. per day, for examplein the treatment of adult humans dosages of from 0.1 to 10 mg./Kg. maybe used.

The compounds and salts of the present invention will normally beadministered orally or by injection and, for this purpose, saidcompounds and salts will usually be utilised in the form of apharmaceutical composition. Such compositions are prepared in a mannerwell known in the pharmaceutical art and normally comprise at least oneactive compound or pharmaceuticallyacceptable salt of the inventionassociated with a pharmaceutically-acceptable carrier therefor. Inmaking the compositions of the present invention, the active ingredientwill usually be mixed with a carrier, or diluted by a carrier, orenclosed within a carrier which may be in the form of a capsule, sachet,paper or other container. When the carrier serves as a diluent, it maybe a solid, semi-solid or liquid material which acts as a vehicle,excipient or medium for the active ingredient. Some examples of suitablecarriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches,gum acacia, calcium phosphate, alginates, tragancanth, gelatin, syrup,methyl cellulose, methyland propyl-hydroxybenzoate, talc, magnesiumstearate or mineral oil. The compositions of the invention may, as iswell-known in the art, be formulated so as to provide quick, sustainedor delayed release of the active ingredient after administration to thepatient.

Depending on the route of administration, the foregoing compositions maybe formulated as tablets, capsules or suspensions for oral use andinjection solutions for parenteral use. Preferably the compositions areformulated in a dosage unit form, each dosage containing from 1 to 200mg. more usually 5 to 100 mg., of the active ingredient.

The following preparation and Examples will further illustrate theinvention. In cases where melting points are not given, support for thestructure of final (title) products was usually obtained by thin-layerchromatography and/or spectral data.

PREPARATION 1α'-Carboxymethyl-β'-carboxyethyl-α-ethylethylmethylsulphide

Ethyl pent-3-enoate (12.6 g, 0.1 mole) J. Org. Chem. 12, 138-154, wasadded dropwise to a solution of methyl thioglycolate (10.6 g, 0.1 mol)and piperidine (0.1 ml) which were stirred together in a three-necked100 ml flask equipped with a dropping funnel, thermometer and condenser.The temperature of the reaction was kept between 40°-50° C., piperidine(0.6 ml) being added in 0.05 ml amounts over a period of 45 minutes.After the addition of pentenoate, the reaction was maintained at 50° C.for 10 minutes. The reaction mixture was then cooled, washed with water,dried over MgSO₄, filtered and the filter pad washed with ether. Thecombined filtrate was evaporated to dryness and the title compoundobtained as a yellow liquid.

EXAMPLE 1 (a) Ethyl 5-ethyl-2-(2-nitroanilino)-thiophene-3-carboxylate

Ethyl 2-amino-5-ethyl-thiophene-3-carboxylate (Ber. 99, 94-100) (40 g,0.2 mol) in dry tetrahydrofuran (150 ml) was stirred under nitrogen andcooled to -40° C. n-Butyl lithium (125 ml of 10.2% w/v solution inhexane, 0.2 mol) was added keeping the temperature below -30° C. Themixture was then stirred at -30° C. for a further 15 minutes. Thissolution was blown by nitrogen through an inverted "U" tube into asolution of o-fluoro-nitrobenzene (28 g, 0.2 mol) in dry tetrahydrofuran(100 ml) maintained at 15°-30° C. The mixture was stirred overnight. Theresulting ink-blue solution was poured into three volumes of ice water,extracted with ether (3 × 500 ml), washed with water (2 × 500 ml), driedand then evaporated to dryness. The deep red oil was dissolved inethanol (200 ml) and chilled overnight. Crystals of the title compoundwere filtered off and dried in vacuo at 50° C.

Recrystallisation from ethanol gave pure product having a m.p. of66°-68° C.

(b) Ethyl 5-ethyl-2-(4-fluoro-2-nitroanilino)-thiophene-3-carboxylate

The title compound was similarly prepared but using2,5-difluoro-nitrobenzene in place of the o-fluoronitrobenzene used inExample 1(a) above, m.p. 90° C. (after recrystallisation from ethanol).

Anal. Calc. for C₁₅ H₁₅ FN₂ O₄ S C: 53.24; H: 4.45; N: 8.28; F: 5.61; S:9.47% Found: C: 53.45; H: 4.75; N: 8.15; F: 5.71; S: 9.75%

Similarly, using the procedure described in Example 1(a), the followingcompounds were prepared. In each case, the nitrobenzene used in place ofthe o-nitrobenzene of Example 1(a) is given, as is the melting point ofthe title compound, together with recrystallisation solvent - indicatedin parenthesis.

(c) Ethyl2-(3,5-difluoro-2-nitroanilino)-5-ethyl-thiophene-3-carboxylate

2,4,6-Trifluoro-nitrobenzene, m.p. 74°-75° C. (EtOH).

(d) Ethyl 5-ethyl-2-(5-fluoro-2-nitroanilino)-thiophene-3-carboxylate

2,4-Difluoro-nitrobenzene, m.p. 87°-88° C. (EtOH).

(e) Ethyl 2-(4-chloro-2-nitroanilino)-5-ethyl-thiophene-3-carboxylate

5-Chloro-2-fluoro-nitrobenzene, m.p. 75°-76.5° C. (EtOH).

(f) Ethyl 2-(2,4-dinitroanilino)-5-ethyl-thiophene-3-carboxylate

2,4-Dinitro-fluorobenzene, 148° C. (EtOH).

(g) Ethyl2-(4-fluoro-2-nitroanilino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate

The title compound was similarly prepared using the process of Example1(a) but using as starting materials 2,5-difluoro-nitrobenzene and ethyl2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate, m.p.140°-142° C. (EtOH).

(h) Ethyl2-(4,5-difluoro-2-nitroanilino)-5-ethyl-thiophene-3-carboxylate

2,4,5-Trifluoro-nitrobenzene, m.p. 105° C. (EtOH).

(i) Methyl 3-(2-nitroanilino)-thiophene-2-carboxylate

The title compound was prepared using the process of Example 1(a) butwith 2-fluoro-nitrobenzene and methyl 3-aminothiophene-2-carboxylate(U.K. Pat. No. 837,086) as starting materials, m.p. 184° C.,(toluene/MeOH, 2:1).

(j) Methyl 3-(4-fluoro-2-nitroanilino)-thiophene-2-carboxylate

The title compound was prepared using the process of Example 1(a) butwith 2,5-difluoronitrobenzene and methyl 3-aminothiophene-2-carboxylateas starting materials, m.p. 172°-175° C. (benzene).

Similarly prepared were:

(k) Ethyl 5-i-propyl-2-(4-fluoro-2-nitroanilino)-thiophene-3-carboxylate(l) Ethyl 5-n-hexyl-2-(4-fluoro-2-nitroanilino)-thiophene-3-carboxylate(m) Ethyl 4-methyl-2-(4-fluoro-2-nitroanilino)-thiophene-3-carboxylate(n) Ethyl4-methyl-5-ethyl-2-(4-fluoro-2-nitroanilino)-thiophene-3-carboxylateEXAMPLE 2 (a) Ethyl 5-ethyl-2-(2-nitroanilino)-thiophene-3-carboxylate

o-Fluoronitrobenzene (56.4 g, 0.4 mol) and ethyl2-amino-5-ethylthiophene-3-carboxylate (100 g, 0.5 mol) were dissolvedin dry dimethylsulphoxide (320 ml). The stirred solution, undernitrogen, was heated in an oil bath. When the internal temperaturereached 60° C., potassium carbonate (55 g, 0.4 mol) was added and themixture stirred at 100° C. until GLC indicated that all theo-fluoronitrobenzene had been consumed (6.5 hours). The mixture was thenpoured onto ice-water, acidified with concentrated hydrochloric acid andextracted with methylene chloride. The combined extracts were washedwith water, dried (MgSO₄) and the solvent evaporated to give a redsemi-solid which was recrystallised from ethanol to give the titleproduct as a solid (m.p. 66°-68° C.).

The following compounds were similarly prepared using the process ofExample 2(a). In each case, the melting point of the title compound, therecrystallisation solvent - indicated in parentheses - and the startingmaterials (when different from those of Example 2(a) are given.

(b) Ethyl 2-(4-chloro-2-nitroanilino)-5-ethyl-thiophene-3-carboxylate

5-Chloro-2-fluoro-nitrobenzene, m.p. 75°-76° C. (EtOH).

(c) Ethyl 2-(2,4-dinitroanilino)-5-ethyl-thiophene-3-carboxylate

2,4-Dinitro-fluorobenzene, m.p. 146°-148° C. (EtOH).

(d) Ethyl5-ethyl-2-(2-nitro-4-trifluoromethylanilino)-thiophene-3-carboxylate

4-Fluoro-3-nitrobenzotrifluoride, m.p. 102° C. (EtOH).

(e) Ethyl 5-ethyl-2-(5-methyl-2-nitroanilino)-thiophene-3-carboxylate

3-Fluoro-4-nitrotoluene, m.p. 55°-57° C. (EtOH).

(f) Ethyl2-(4-difluoromethyl-2-nitroanilino)-5-ethyl-thiophene-3-carboxylate

5-Difluoromethyl-2-fluoro-nitrobenzene, m.p. 88°-90° C. (EtOH).

(g) Methyl2-(4-N,N-dimethylsulphonamido-2-nitroanilino)-5-ethyl-thiophene-3-carboxylate

5-N,N-Dimethylsulphonamido-2-fluoro-nitrobenzene and methyl2-amino-5-ethyl-thiophene-3-carboxylate, m.p. 166°-168° C. (EtOH).

(h) Methyl 5-ethyl-2-(4-methoxy-2-nitroanilino)-thiophene-3-carboxylate

2-Fluoro-5-methoxy-nitrobenzene and methyl2-amino-5-ethyl-thiophene-3-carboxylate, m.p. 125°-127° C. (EtOH).

(i) Ethyl 2-(4-fluoro-2-nitroanilino)-thiophene-3-carboxylate

2,5-Difluoro-nitrobenzene and ethyl 2-amino-thiophene-3-carboxylate,m.p. 125° C. (EtOH).

(j) Ethyl5-ethyl-2-(4-methylthio-2-nitroanilino)-thiophene-3-carboxylate

4-Fluoro-3-nitro-thioanisole and ethyl2-amino-5-ethyl-thiophene-3-carboxylate.

(k) Ethyl 2-(2-chloro-6-nitroanilino)-5-ethyl-thiophene-3-carboxylate

Ethyl 2-amino-5-ethyl-thiophene-3-carboxylate and3-chloro-2-fluoronitrobenzene, m.p. 67°-70° C. (EtOH).

(l) Ethyl5-ethyl-2-(2-trifluoromethyl-6-nitroanilino)-thiophene-3-carboxylate

Ethyl 2-amino-5-ethylthiophene-3-carboxylate and2-fluoro-3-trifluoromethylnitrobenzene, m.p. 72°-73° C. (EtOH).

(m) Methyl 3-(4-chloro-2-nitroanilino)-thiophene-2-carboxylate

5-Chloro-2-fluoro-nitrobenzene and methyl3-amino-thiophene-2-carboxylate, m.p. 207°-208° C. (EtOAc/Hexane).

(n) Methyl 5-methyl-2-(2-nitro-4-fluoroanilino)-thiophene-3-carboxylate

Methyl 2-amino-5-methyl-thiophene-3-carboxylate and2,5-difluoronitrobenzene, m.p. 149°-151° C. (EtOH).

(o) Ethyl 2-(4-bromo-2-nitroanilino)-5-ethyl-thiophene-3-carboxylate

Ethyl 2-amino-5-ethyl-thiophene-3-carboxylate and5-bromo-2-fluoronitrobenzene, m.p. 76°-78° C. (EtOH).

(p) Methyl 2-(4-fluoro-2-nitroanilino)-5-phenyl-thiophene-3-carboxylate

Methyl 2-amino-5-phenyl-thiophene-3-carboxylate and2,5-difluoronitrobenzene, m.p. 150° C. (CH₂ Cl₂).

(q) 5-Ethyl-2-(2-nitroanilino)-thiophene-3-carboxylic acid

Ethyl 5-ethyl-2-(2-nitroanilino)-thiophene-3-carboxylate (6.0 g)dissolved in ethanol (100 ml) and water (50 ml) and heated to 60° C.with stirring. Sodium hydroxide (5N,50 ml) was then added and thetemperature maintained for 16 hours. The reaction mixture was cooled anddiluted with water (500 ml), and solid title product filtered off, m.p.189°-191° C. (EtOAc).

(r) 5-Ethyl-2-(4-fluoro-2-nitroanilino)-thiophene-3-carboxylic acid

The title compound was similarly prepared from ethyl5-ethyl-2-(4-fluoro-2-nitroanilino)-thiophene-3-carboxylate but using areaction temperature of 25° C., m.p. 198°-200° C. (EtOAc).

(s) Methyl 5-Ethyl-3-(4-fluoro-2-nitroanilino)-thiophene-2-carboxylateEXAMPLE 3 (a) Methyl 3-(4-fluoro-2-nitroanilino)-thiophene-4-carboxylate

3-Carboxymethyl-4-aminothiophene hydrochloride J.A.C.S. 68, 2232 (1946)(48.5 g, 0.25 mol) was dissolved in a minimum of water and shaken in thepresence of saturated sodium bicarbonate solution and ether. The etherextract was dried with MgSO₄, filtered and evaporated to an oil,dissolved in dimethylformamide (DMF), 2-methoxyethanol, ordimethylsulphoxide (DMSO) (anhydrous), preferably the latter (100 ml).To this stirred solution at 100° C., under nitrogen, was added2,5-difluoronitrobenzene (40 g, 0.25 mol) and triethylamine (35 ml), thereaction was kept at these conditions for an hour (under reflux) andmore triethylamine (35 ml) added. The reaction was then heated, withstirring under nitrogen for a further 40 hours.

The chilled mixture was poured into saturated brine (1-1/2 liters) withstirring, in the presence of ethyl acetate, the two-phase mixture wasfiltered. The organic phase was run off, washed with brine, dried withMgSO₄, filtered and evaporated to a brown gum. This gum was dissolved ina minimum of ethyl acetate and vacuum-filtered through a pad of"Florisil" (trade mark) contained in a sintered funnel, the pad waswashed with ethyl acetate until all the product had been removed, thefiltrates bulked, evaporated to an oil, dissolved in cold ethanol (250ml) and left at 0° C. for 24 hours. The redorange crystalline productoccasionally contained traces of brown tar, but it was found that thiscould be removed by adding a little ethyl acetate and triturating. Thecrystals so obtained were filtered, washed with ethanol, 40°-60° C.petrol, and then dried under vacuo to give the title compound as a solidproduct, m.p. 164° C.

(b) Methyl 3-(2-nitro-4-trifluoromethylanilino)-thiophene-4-carboxylate

The title compound was similarly prepared using the process described inExample 3(a) above, m.p. 175° C. (EtOH).

(c)2-(4-Fluoro-2-nitroanilino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-nitrile

2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-nitrile (3.6 g, 0.02 mol)and 2,5-difluoronitrobenzene (3.2 g, 0.02 mol) in dry DMSO (20 ml) wasstirred and heated on an oil bath. When the internal temperature reached60° C., potassium carbonate (2.76 g, 0.02 mol) was added and the mixturethen stirred at 100° C. for 5 hours. The reaction mixture was pouredonto ice-water, acidified and extracted with methylene chloride. Thecombined extracts were washed with water, dried (MgSO₄) and the solventremoved in vacuo, m.p. 137°-139° C. (EtOAc).

Similarly, the following compounds were prepared using2-amino-5-ethyl-thiophene-3-nitrile.

(d) 5-Ethyl-2-(4-fluoro-2-nitroanilino)-thiophene-3-nitrile (e)5-Ethyl-2-(4-methoxy-2-nitroanilino)-thiophene-3-nitrile (f)5-Ethyl-2-(4-methylthio-2-nitroanilino)-thiophene-3-nitrile (g)5-Ethyl-2-(2-nitro-4-trifluoromethylanilino)-thiophene-3-nitrile EXAMPLE4 (a) 3-(4-Chloro-2-nitroanilino)-2,5-dihydrothiophene-4-nitrile

3-Cyanotetrahydrothiophen-4-one (Dutch Patent Application No. 66,04742)(38.1 g, 0.25 mol) and 4-chloro-2-nitroaniline (51.8 g, 0.28 mol) weredissolved in refluxing toluene (˜ 200 ml) in a three-necked flask (500ml) fitted with a Dean and Stark apparatus. A few drops of borontrifluoride etherate were added and the reaction was left to reflux for4 hours, the water formed being tapped off.

The reaction mixture was left to cool whereupon a brown solidprecipitated and was filtered off. The solid was recrystallised fromabsolute ethanol using activated charcoal as a decolouriser, and theorange crystalline solid which was obtained was filtered, washed withethanol and then dried at 50° C. under vacuum. The dried solid soobtained was the title compound which had a melting point of 154°-155°C.

(b) 3-(4-Methylthio-2-nitroanilino)-2,5-dihydrothiophene-4-nitrile

The title compound was obtained using a similar procedure to thatoutlined in Example 4(a) above, m.p. 141°-142° C. (EtOH).

(c) 4-(4-Fluoro-2-nitroanilino)-2-ethyl-2,5-dihydrothiophene-3-nitrileEXAMPLE 5 (a) 3-(4-Chloro-2-nitroanilino)-thiophene-4-nitrile

3-(4-Chloro-2-nitroanilino)-2,5-dihydrothiophene-4-nitrile (14.09 g,0.05 mol) dissolved in xylene (150 ml) was added to a solution ofchloranil (12.3 g, 0.05 mol) in hot xylene (100 ml). The mixture wasallowed to reflux for two hours. After cooling, the xylene wasevaporated off under vacuum to leave a red-brown solid which wastriturated with methanol to give a brick-red solid. The solid wasrecrystallised from hot methanol to give red crystals which werefiltered off, washed with methanol and dried at 50° C. under vacuum. Thedried product so obtained was the title compound, m.p. 214° C.

(b) 3-(4-Methylthio-2-nitroanilino)-thiophene-4-nitrile

was similarly prepared, m.p. 167°-169° C. (MeOH).

(c) 4-(4-Fluoro-2-nitroanilino)-2-ethyl-thiophene-3-nitrile EXAMPLE 6(a) Ethyl 2-(2-aminoanilino)-5-ethyl-thiophene-3-carboxylate

Ethyl 5-ethyl-2-(2-nitroanilino)-thiophene-3-carboxylate (20.7 g) inethanol (150 ml) was catalytically reduced over 10% palladium oncharcoal (2.0 g) at 60 p.s.i. The catalyst was removed by filtration andthe solvent removed by distillation in vacuo. The title product soobtained had a melting point of 50°-52° C. (hexane).

The following compounds were similarly prepared:

(b) Ethyl 2-(2-amino-4-fluoroanilino)-5-ethyl-thiophene-3-carboxylatem.p. 82°-84° C. (hexane). (c) Ethyl2-(2-amino-3,5-difluoroanilino)-5-ethyl-thiophene-3-carboxylate m.p.106° C. (EtOH). (d) Ethyl2-(2-amino-5-fluoroanilino)-5-ethyl-thiophene-3-carboxylate m.p.100°-101° C. (EtOH). (e) Ethyl2-(2-amino-4-chloroanilino)-5-ethyl-thiophene-3-carboxylate m.p.119°-121° C. (EtOH). (f) Ethyl2-(2,4-diaminoanilino)-5-ethyl-thiophene-3-carboxylate, m.p. 152°-5° C.(hexane). (g) Ethyl2-(2-amino-4-trifluoromethylanilino)-5-ethyl-thiophene-3-carboxylate (h)Ethyl 2-(2-amino-5-methylanilino)-5-ethyl-thiophene-3-carboxylate (i)Ethyl2-(4-difluoromethyl-2-nitroanilino)-5-ethyl-thiophene-3-carboxylate (j)Methyl2-(2-amino-4-N,N-dimethylsulphonamidoanilino)-5-ethyl-thiophene-3-carboxylate(k) Methyl 2-(2-amino-4-methoxyanilino)-5-ethyl-thiophene-3-carboxylate(l) Ethyl2-(2-amino-4-fluoroanilino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate(m) Ethyl 2-(2-amino-4-fluoroanilino)-thiophene-3-carboxylate (n) Ethyl2-(2-amino-4-methylthioanilino)-5-ethyl-thiophene-3-carboxylate (o)Methyl 3-(2-aminoanilino)-thiophene-2-carboxylate

m.p. 102° C.

The title compound was prepared by the reduction of methyl3-(2-nitroanilino)-thiophene-2-carboxylate.

(p) Methyl 3-(2-amino-4-fluoroanilino)-thiophene-2-carboxylate

The title compound was similarly prepared by the reduction of methyl3-(4-fluoro-2-nitroanilino)-thiophene-2-carboxylate.

(q) Methyl 3-(2-amino-4-chloroanilino)-thiophene-2-carboxylate (r)Methyl 2-(2-amino-4-fluoroanilino)-5-methyl-thiophene-3-carboxylate

m.p. 116°-118° C.

(s) Ethyl 5-i-propyl-2-(4-fluoro-2-aminoanilino)-thiophene-3-carboxylate(t) Ethyl 5-n-hexyl-2-(4-fluoro-2-aminoanilino)-thiophene-3-carboxylate(u) Ethyl 4-methyl-2-(4-fluoro-2-aminoanilino)-thiophene-3-carboxylate(v) Ethyl4-methyl-5-ethyl-2-(4-fluoro-2-aminoanilino)-thiophene-3-carboxylate (w)2-(2-Aminoanilino)-5-ethyl-thiophene-3-carboxylic acid

5-Ethyl-2-(2-nitroanilino)-thiophene-3-carboxylic acid (8.0 g, 0.027mol) in ethanol (150 ml) was catalytically reduced over 10% palladium oncharcoal (900 mg) at 60 p.s.i. The catalyst was removed by filtrationand the solvent removed by distillation in vacuo to give the titlecompound.

(x) Methyl 5-ethyl-3-(2-amino-4-fluoroanilino)-thiophene-2-carboxylateEXAMPLE 7 Ethyl2-(2-amino-4-nitroanilino)-5-ethyl-thiophene-3-carboxylate

Ethyl 2-(2,4-dinitroanilino)-5-ethyl-thiophene-3-carboxylate (0.5 g) in6N ammonia (25 ml) and ethanol (10 ml) was stirred at reflux temperatureand hydrogen sulphide gas passed in over a period of 2 hours. Thereaction mixture was cooled to room temperature and the title compoundobtained as a yellow precipitate filtered off, washed with water, anddried in vacuo, m.p. 174°-176° C. (EtOAc).

EXAMPLE 8 Ethyl2-(2-amino-4-bromoanilino)-5-ethyl-thiophene-3-carboxylate

Ethyl 2-(4-bromo-2-nitroanilino)-5-ethyl-thiophene-3-carboxylate (0.4 g,0.001 mol) was added to powdered zinc (0.4 g) and ammonium chloride (0.4g) in water (10 ml) and stirred at 50° C. for 24 hours. The reactionmixture was filtered and the recovered solid washed successively withwater and ethyl acetate. The organic phase was separated, washed withwater, dried (MgSO₄) and evaporated in vacuo to give the title compound.

EXAMPLE 9 (a) Methyl3-(2-Aminoanilino)-2,5-dihydrothiophene-4-carboxylate

3-Carboxymethyltetrahydrothiophen-4-one (48.06 g, 0.3 m) ando-phenylenediamine (32.4 g, 0.3 m) were dissolved in boiling ethanol(500 ml), to which a few drops of acetic acid had been added. Thesolution was then heated under reflux, in a nitrogen atmosphere for fourhours and left to cool. The crystalline material so obtained wasfiltered off, washed with ethanol and dried under vacuum. The productwas recrystallised from absolute ethanol using activated charcoal as adecolouriser, a yellow solution being obtained from which white needlescrystallised out. The white crystalline solid was filtered off, washedwith ethanol and dried under vacuum to give the title product, m.p. 101°C.

(b) Methyl3-(2-amino-4,5-dichloroanilino)-2,5-dihydrothiophene-3-carboxylate

The title compound, m.p. 162° C., was obtained by a process similar tothat of Example 9(a).

EXAMPLE 10 (a) 3-(2-Aminoanilino)thiophene-4-carboxylate

Methyl 3-(2-aminoanilino)-2,5-dihydrothiophene-4-carboxylate (25.03 g,0.1 mol) and chloranil (24.6 g, 0.1 mol) were refluxed together inxylene (900 ml) for two hours. The solvent was then evaporated off,under vacuum to leave a dark brown solid which was triturated with ethylacetate to give a light brown solid, which was filtered, washed withethyl acetate and dried under vacuum to give the title product, meltingpoint 120°-122° C.

Similarly prepared was:-

(b) Methyl 3-(2-amino-4,5-dichloroanilino)-thiophene-4-carboxylate m.p.162°-163° C. EXAMPLE 11 Methyl3-(2-aminoanilino)-thiophene-4-carboxylate

Methyl 3-(2-aminoanilino)-2,5-dihydrothiophene-4-carboxylate (2.5 g,0.001 mol) was added to a flask containing palladium on charcoalcatalyst (5%, 200 mg) in cyclohexene (or norbornadiene or norbornylene)(50 ml) and the reaction was heated at reflux with stirring for 4 hours,the reaction being followed by t.l.c.

The reaction mixture was then cooled, the solvent evaporated off undervacuum to leave a dark brown oil which was column chromatographed usinga "Florisil" column and chloroform to give the title product as anorange solid. m.p. 120°-122° C.

EXAMPLE 12 (a)3-(2-Amino-5-trifluoromethylanilino)-2,5-dihydro-thiophene-4-nitrile

4-Trifluoromethyl-o-phenylenediamine (24 g, 0.136 mol) and3-keto-4-nitrile-2,5-dihydrothiophene (17.3 g, 0.136 mol) were dissolvedin 200 ml of warm ethanol, acetic acid (3 ml) was added and the solutionheated under reflux for 24 hours, then left to cool. The title productwas thus obtained as a white solid which was filtered off and combinedwith solid obtained from evaporating the filtrate to small bulk, andcooling, m.p. 189° C.

Similarly prepared were :-

(b) 3-(2-Amino-5-chloroanilino)-2,5-dihydrothiophene-4-nitrile m.p.164°-165° C. (c) 3-(2-Aminoanilino)-2,5-dihydrothiophene-4-nitrile

3-Keto-4-cyanotetrahydrothiophene (80 g, 0.629 mol) ando-phenylenediamine (68 g, 0.629 mol) were dissolved by heating in 1.5liters of industrial methylated spirit. To the solution, glacial aceticacid (3 ml) was added, the solution then being heated under reflux withmechanical stirring for 24 hours. The solution was then chilled andfiltered to give the title product as a solid, m.p. 163° C.

EXAMPLE 13 (a) 10-Amino-7-chloro-4H-thieno[3,4-b][1,5]benzodiazepine

3-(4-Chloro-2-nitroanilino)-thiophene-4-nitrile (17.18 g, 0.06 mol) washydrogenated in ethanol (300 ml) and ethyl acetate (100 ml) using apalladium/charcoal catalyst (3.5 g, 10%) in a Parr hydrogenator to give3-(4-Chloro-2-aminoanilino)-thiophene-4-nitrile. After two hours, thereaction was complete, the catalyst was filtered off and the solutionwas evaporated to dryness under vacuum.

The light brown solid obtained was redissolved in absolute ethanol (100ml) in a three-necked flask (500 ml). Concentrated hydrochloric acid (12ml) was added dropwise carefully to the stirred solution. The alcoholicsolution was then allowed to reflux for approximately 24 hours. Sodiumhydroxide solution (10%, 60 ml) was then added dropwise to the cooledsolution until the solution was slightly basic. During addition, aprecipitate of the title compound was formed, which was filtered off togive a pale yellow/brown solid, which was washed with water and dried at50° C. under vacuum, m.p. 239°-240° C.

Similarly prepared were :-

(b) 10-Amino-7-methylthio-4H-thieno[3,4-b][1,5]benzodiazepine, m.p.195°-7° C.

(c)12-Amino-9-fluoro-6H-1,2,3,4-tetrahydrobenzothieno[2,3-b][1,5]benzodiazepine

(d) 10-Amino-2-ethyl-7-fluoro-4H-thieno[2,3-b][1,5]benzodiazepine

(e) 10-Amino-2-ethyl-7-methoxy-4H-thieno[2,3-b][1,5]benzodiazepine

(f) 10-Amino-2-ethyl-7-methylthio-4H-thieno[2,3-b][1,5]benzodiazepine

(g)10-Amino-2-ethyl-7-trifluoromethyl-4H-thieno[2,3-b][1,5]benzodiazepine

(h) 10-Amino-1-ethyl-7-fluoro-4H-thieno[3,4-b][1,5]benzodiazepine

EXAMPLE 14 (a) 10-Amino-4H-2,5-dihydrothieno[3,4-b][1,5]benzodiazepinehydrochloride

3-(2-Aminoanilino)-2,5-dihydrothiophene-4-nitrile (84.5 g, 0.39 mol) wassuspended by mechanical stirring in hot industrial methylated spirit(1.5 liters). Concentrated hydrochloric acid (57 ml, 0.66 mol) was addeddropwise, the solution was stirred at reflux temperature for 1 hour thenchilled, and the solid so obtained filtered, washed with a littleindustrial methylated spirit, petrol (40°-60° C.) and dried at 50° C.under vacuum. The title compound so obtained had a melting point of 292°C. (decomp.).

(b) 10-Amino-4H-2,5-dihydrothieno[3,4-b][1,5]benzodiazepine

The hydrochloride of (a) above (54.5 g) was suspended in 1 liter ofchloroform with mechanical stirring and 500 ml. of 10% w/w sodiumhydroxide was added in one portion. The suspension was stirred for twohours whereupon the title compound was obtained as a white solid. Thiswas filtered off, washed with water, ethanol, ether and dried undervacuum to give the free base, m.p. 240°-250° C. (decomp.).

(c) 9,10-Dihydro-4H-2,5-dihydro-thieno[3,4-b][1,5]benzodiazepin-10-one

Methyl 3-(2-aminoanilino)-2,5-dihydrothiophene-4-carboxylate (0.5 g,0.002 mol) in dry DMSO (2 ml) was added to a solution of 50% w/w sodiumhydride/oil suspension (300 mg) in dry DMSO at 90° C. under nitrogen.When effervescence had ceased, the solution was stirred for two hoursand poured onto 300 ml. of ice/brine. The solution was then extractedinto ethyl acetate, the extract dried with magnesium sulphate, filteredand evaporated to small bulk. Ether was added to the suspension and thiswas filtered. The filtrate was evaporated to dryness and triturated withchloroform to yield the title compound as a yellow solid, m.p. 210° C.(decomposition).

EXAMPLE 15 (a) 10-Amino-4H-2,5-dihydrothieno[3,4-b][1,5]benzodiazepine

3-Cyanotetrahydrothiophen-4-one (80 g, 0.629 mol) and o-phenylenediamine(68 g, 0.629 mol) were dissolved in 1.5 liters of industrial methylatedspirit by heating under reflux with stirring, acetic acid (3 ml) wasthen added and the mixture heated under reflux with stirring for 5hours. To the cooled solution there was carefully added concentratedhydrochloric acid (92 ml, 1.08 mol) with stirring. The solution was thenheated under reflux for one hour and to the chilled, stirred solution ofhydrochloride there was added 10% w/w sodium hydroxide (500 ml)dropwise, keeping the temperature below 40° C. The solution was thenstirred for one hour, the solid filtered off, washed with water,ethanol, acetone, ether, dried under vacuum. The dried product, whichwas the title compound, had an m.p. of 230°-240° C. (decomp.).

(b) 10-Amino-4H-thieno[3,4-b][1,5]benzodiazepine

10-Amino-4H-2,5-dihydrothieno[3,4-b][1,5]benzodiazepine (43 g, 0.198mol) was suspended with mechanical stirring in boiling xylene (1 liter).To this was added chloranil (49 g), the suspension being stirred atreflux temperature for 2-6 hours and then left to stand overnight atroom temperature. The suspension was then filtered, and the solid washedwith xylene until the washings were colourless. It was then dried on afilter funnel. The dried black solid thus obtained was suspended in hotwater (200 ml) and 5M hydrochloric acid (36 ml) was added to form a redsolution which was boiled for 10 minutes.

The solution was then filtered and residual tar extracted with another36 ml of 5M HCl in water (200 ml) and refiltered. The collected hotfiltrates were added dropwise to an ice-cooled solution of sodiumhydroxide (14.4 g, 0.36 mol) in water (100 ml) at such a rate that thetemperature of 40° C. was not exceeded. The solution was stirred for 1hour, filtered, the solid being washed with water and dried under vacuumat 50° C. The dried title compound thus obtained had a melting point of190° C. (decomp).

EXAMPLE 1610-Amino-6-trifluoromethyl-4H-2,5-dihydrothieno[3,4-b][1,5]benzodiazepine

3-(2-Amino-5-trifluoromethylanilino)-4-cyano-2,5-dihydrothiophene (10.5g, 0.0368 mol) was dissolved in industrial methylated spirit (100 ml) byheating, and to this stirred solution, a solution of concentratedhydrochloric acid (3.2 ml, 0.0368 mol) was carefully added. The redsolution so formed was heated under reflux for 1 hour. To the chilled,stirred solution, a solution of sodium hydroxide (1.6 g) in water (10ml) was added dropwise, the temperature being kept below 40° C. The buffamidine thus formed was filtered off, washed with water, ethanol,40°-60° C. petrol, and then dried at 50° C. under vacuum. The filtratewas diluted with an excess of water and the solid so produced wasfiltered off and dried and included with the other solid. The titlecompound thus produced had a melting point of 200°-210° C. (decomp.).

Similarly prepared was :-

(b) 10-Amino-6-chloro-4H-2,5-dihydrothieno[3,4-b][1,5]benzodiazepineEXAMPLE 17

The product of Examples 16(a) and 16(b) were "aromatised" to

(a) 10-Amino-6-trifluoromethyl-4H-thieno[3,4-b][1,5]benzodiazepine, m.p.178° C. (dcc); and

(b) 10-Amino-6-chloro-4H-thieno[3,4-b][1,5]benzodiazepine, using theprocess of Example 15(b).

EXAMPLE 18 (a)9,10-Dihydro-2-ethyl-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

Sodium methyl sulphinyl carbanion was generated by stirring sodiumhydride (7.2 g, 0.15 mol) in dry dimethylsulphoxide (100 ml) at 70° C.until gas evolution ceased. Ethyl2-(2-aminoanilino)-5-ethyl-thiophene-3-carboxylate (14.5 g, 0.05 mol) indry dimethylsulphoxide (50 ml) was added and stirred for 15 minutes. Themixture was poured onto ice-water (600 ml) and stirred for fifteenminutes. The solid was filtered off, washed well with water, dried,washed with carbon tetrachloride and dried in vacuo at 60° C. The driedproduct which was the title compound had a melting point of 218°-220° C.(CHCl₃).

(b)2-Ethyl-7-fluoro-9,10-dihydro-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

The title compound, m.p. 210°-212° C., was similarly prepared from ethyl2-(2-amino-4-fluoroanilino)-5-ethyl-thiophene-3-carboxylate. The titlecompound was recrystallised from ethanol.

The following compounds were also similarly prepared using the processof Example 18(a). In each case, the starting thiophene material, meltingpoint of title product, and recrystallisation solvent are indicated.

(c)6,8-Difluoro-9,10-dihydro-2-ethyl-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

Ethyl 2-(2-amino-3,5-difluoroanilino)-5-ethyl-thiophene-3-carboxylate,m.p. 230°-232° C. (CHCl₃).

(d)9,10-Dihydro-2-ethyl-6-fluoro-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

Ethyl 2-(2-amino-5-fluoroanilino)-5-ethyl-thiophene-3-carboxylate, m.p.255°-257° C. (EtOAc).

(e)7-Chloro-9,10-dihydro-2-ethyl-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

Ethyl 2-(2-amino-4-chloroanilino)-5-ethyl-thiophene-3-carboxylate. m.p.216°-218° C. (EtOAc).

(f)7-Amino-9,10-dihydro-2-ethyl-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

Ethyl 2-(2,4-diaminoanilino)-5-ethyl-thiophene-3-carboxylate, m.p. 230°C. (decomp.) (CHCl₃ /MeOH).

(g)9,10-Dihydro-2-ethyl-6-methyl-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

2-(2-Amino-5-methylanilino)-5-ethyl-thiophene-3-carboxylate m.p.205°-207° C. (EtOAc).

(h)9,10-Dihydro-7-N,N-dimethylsulphonamido-2-ethyl-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

Methyl2-(2-amino-4-N,N-dimethylsulphonamidoanilino)-5-ethyl-thiophene-3-carboxylate,m.p. 258°-260° C. (EtOAc).

(i)9,10-Dihydro-2-ethyl-7-nitro-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

Ethyl 2-(2-amino-4-nitroanilino)-5-ethyl-thiophene-3-carboxylate, m.p.264°-266° C. (EtOAc).

(j) 9,10-Dihydro-7-fluoro-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

Ethyl 2-(2-amino-4-fluoroanilino)-thiophene-3-carboxylate, m.p.235°-240° C. (CCl₄ /hexane).

(k)9-Fluoro-6H-1,2,3,4,11,12-hexahydrobenzothieno[2,3-b][1,5]benzodiazepin-12-one

Ethyl2-(2-amino-4-fluoroanilino)4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylatem.p. 238° C. (EtOAc).

(l)9,10-Dihydro-2-ethyl-7-trifluoromethyl-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

Ethyl2-(2-amino-4-trifluoromethylanilino)-5-ethyl-thiophene-3-carboxylate.

(m)9,10-Dihydro-2-ethyl-7-methoxy-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

Ethyl 2-(2-amino-4-methoxyanilino)-5-ethyl-thiophene-3-carboxylate.

(n)9,10-Dihydro-2-ethyl-7-methylthio-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

Ethyl 2-(2-amino-4-methylthioanilino)-5-ethyl-thiophene-3-carboxylate.

(o)6,7-Difluoro-9,10-dihydro-2-ethyl-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

Ethyl 5-ethyl-2-(4,5-difluoro-2-nitroanilino)-thiophene-3-carboxylate,m.p. 290° C.

(p)9,10-Dihydro-7-fluoro-2-phenyl-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

m.p. 250°-252° C. (dec.) (EtOAc).

(q)9,10-Dihydro-7-fluoro-2-methyl-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

m.p. 250°-252° C. (EtOAc).

(r) 9,10-Dihydro-4H-thieno[3,2-b][1,5]benzodiazepin-10-one

Methyl 3-(2-aminoamilino)-thiophene-2-carboxylate, m.p. 226° C. (CCl₄).

(s) 9,10-Dihydro-7-fluoro-4H-thieno[3,2-b][1,5]benzodiazepin-10-one

Methyl 3-(2-amino-4-fluoroanilino)-thiophene-2-carboxylate, m.p.225°-230° C. (EtOAc).

(t) 7-Chloro-9,10-dihydro-4H-thieno[3,2-b][1,5]benzodiazepin-10-one

Methyl 3-(2-amino-4-chloroanilino)-thiophene-2-carboxylate, m.p.255°-256° C. (EtOAc).

(u) 9,10-Dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one

m.p. 233°-234° C. p (v)9,10-Dihydro-7-fluoro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one

Melting point 238° C. (decomposition).

(w) 6,7-Dichloro-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-oneMelting point 284°-287° C.

(x)2-i-Propyl-7-fluoro-9,10-dihydro-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

(y)2-n-Hexyl-7-fluoro-9,10-dihydro-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

(z)1-Methyl-7-fluoro-9,10-dihydro-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

(aa)1-Methyl-2-ethyl-7-fluoro-9,10-dihydro-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

(bb)2-Ethyl-7-fluoro-9,10-dihydro-4H-thieno[3,2-b][1,5]benzodiazepin-10-one

(cc) 2-Ethyl-9,10-dihydro-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

5-Ethyl-2-(2-aminoanilino)-thiophene-3-carboxylic acid was dissolved intetrahydrofuran (distilled from lithium aluminium hydride) (200 ml) andsolid dicyclohexylcarbodiimide (5.7 g, 0.027 mol) added. The mixture wasstirred under a nitrogen atmosphere for 16 hours and the solution thusformed filtered and evaporated to dryness. The residue was boiled withcarbon tetrachloride and allowed to crystallise to yield the titlecompound, m.p. 218°-220° C. (CHCl₃).

EXAMPLE 19 (a)7-Chloro-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one

10-Amino-7-chloro-4H-thieno[3,4-b][1,5]benzodiazepine (4 g, 0.15 mol)was dissolved in the minimum of water (100 ml) to which was addedpotassium carbonate (13.0 g) in water (20 ml). Absolute ethanol (40 ml)was then added to redissolve the amidine and the reaction mixture gentlyrefluxed for 17 hours, during the last hour of which, the ethanol wasslowly distilled off.

The reaction mixture was then allowed to cool, and concentratedhydrochloric acid added dropwise to the solution, in the presence ofethyl acetate, until the solution was slightly acidic. The aqueous phasewas extracted with ethyl acetate, dried over MgSO₄ and the bulkedextracts evaporated to dryness under vacuum, the title product beingobtained as a light brown solid. The solid was triturated with ether,filtered and dried at 50° C. under vacuum to give a yellow solid, m.p.212°-213° C.

Using the hydrolytic procedure of Example 19(a) the following otheramides were obtained :-

(b) 9,10-Dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one

Melting point 234° C. (decomp.).

(c) 9,10-Dihydro-7-methylthio-4H-thieno[3,4-b][1,5]benzodiazepin-10-one

(d)9,10-Dihydro-6-trifluoromethyl-4H-thieno[3,4-b][1,5]benzodiazepin-10-one,m.p. 213° C.

(e)9,10-Dihydro-2-ethyl-7-fluoro-4H-thieno[2,3-b][1,5]benzodiazepin-10-onem.p. 211° C.

(f)9,10-Dihydro-2-ethyl-7-fluoro-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

(g)9,10-Dihydro-2-ethyl-7-methylthio-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

(h)9,10-Dihydro-2-ethyl-7-trifluoromethyl-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

(i)9-Fluoro-6H-1,2,3,4,11,12-hexahydrobenzothieno[2,3-b][1,5]benzodiazepin-12-one

(j)9,10-Dihydro-2-ethyl-6-trifluoromethyl-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

(k) 1-Ethyl-7-fluoro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one

EXAMPLE 20 9,10-Dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one

9,10-Dihydro-4H-2,5-dihydrothieno[3,4-b][1,5]benzodiazepin-10-one (0.33g) was stirred in cyclohexene (norbornadiene or norbornylene) at refluxtemperatures in the presence of a palladium on charcoal catalyst (0.1 g,5%), the reaction being followed by t.l.c. measurements.

The reaction mixture was then cooled, the solvent evaporated off undervacuum to leave dark brown solid which was column chromatographed usinga "Florisil" column and 5% methanol in chloroform to give the titlecompound as a pale yellow solid, m.p. 230°-232° C.

EXAMPLE 217-N-Acylamino-9,10-dihydro-2-ethyl-4H-thieno[2,3b-b][1,5]benzodiazepin-10-one

7-Amino-9,10-dihydro-2-ethyl-4H-thieno[2,3-b][1,5]-benzodiazepin-10-one(100 mg) was suspended in methylene chloride (5 ml) and triethylamine(0.1 ml). Acetic anhydride (10.1 ml) was added and the reaction mixturestirred for 18 hours. The precipitate was filtered off, washed withwater, dried in vacuo at 60° C. to give the title compound as a solid,m.p. 264° C.

EXAMPLE 223-Chloro-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one

4H-Thieno[3,4-b][1,5]benzodiazepin-10-one (4.32 g. 0.02 mol) in hotdichloromethane was reacted with stirring, with N-chlorosuccinimide (3.0g, 0.025 mol) in the presence of a trace of benzoyl peroxide. Afterrefluxing for 1 hour the hot solution was filtered. The blue residue waswashed with three quantities of hot ethyl alcohol which were combinedand bulked with the dichloromethane filtrate and evaporated to a brownsolid. Soxhlet extraction with benzene and subsequent washing with K₂CO₃ solution, drying and evaporation yielded the title compound as abuff solid m.p. 229° C.

EXAMPLE 231-Acetyl-9,10-dihydro-2-ethyl-7-fluoro-4H-thieno[2,3-b][1,5]benzodiazepin-10-one

To a stirred solution of9,10-dihydro-2-ethyl-7-fluoro-4H-thieno[2,3-b][1,5]benzodiazepin (0. 26g, 0.001 mol) in acetyl chloride (3 ml) was added with stirring stannicchloride (2 drops). The reaction was diluted with benzene (5 ml) andstirred for 18 hours at room temperature. The reaction mixture wasdiluted with water and extracted into chloroform, the chloroformextracts were washed with water, dried (MgSO₄) and evaporated in vacuoto give the title product as a solid, m.p. 215°-218° C. (MeOH/hexane).

EXAMPLE 24 (a)9,10-Dihydro-2-ethyl-7-fluoro-4H-thieno[2,3-b][1,5]benzodiazepin-10-thione

9,10-Dihydro-2-ethyl-7-fluoro-4H-thieno[2,3-b[1,5]benzodiazepin-10-one(20 g, 0.076 mol) was added to a stirred solution of phosphoruspentasulphide (17 g, 0.076 mol) in dry pyridine (400 ml). The solutionwas stirred at gentle reflux for 1.5 hours, poured onto ice-water,stirred for 1 hour, filtered, washed with cold water and dried.Recrystallisation from EtOH/water gave the title compound as bronzeplates m.p. 203-206° C.

(b) 9,10-Dihydro-2-ethyl-4H-thieno[2,3-b][1,5]benzodiazepin-10-thione

The title compound was similarly prepared using the process of Example24(a) with9,10-dihydro-2-ethyl-4H-thieno[2,3-b][1,5]benzodiazepin-10-one asstarting material, m.p. 233-236° C. (EtOH-H₂ O).

Similarly prepared were:

(c)9,10-Dihydro-2-ethyl-7-nitro-4H-thieno[2,3-b][1,5]benzodiazepin-10-thione

(d) 9,10-Dihydro-4H-thieno[2,3-b][1,5]benzodiazepin-10-thione, m.p. 221°C.

Other amides of Example 18 were similarly converted into their thioamidederivatives using the procedure of Example 24(a). In each case, theidentification and confirmation of the final product was effected bymeans of t.l.c. and microanalytical evidence.

EXAMPLE 25 (a)2-Ethyl-6-fluoro-10-(4-methyl-1-piperzinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

9,10-Dihydro-2-ethyl-6-fluoro-4H-thieno[2,3-b][1,5]benzodiazepin-10-one(0.5 g), phosphorous oxychloride (4 ml) and N,N-dimethylaniline (0.15ml) were refluxed for 3 hours. The reaction mixture was evaporated invacuo and the residue evaporated twice more with xylene. The crude iminochloride was dissolved in absolute dioxan (1 ml) and N-methyl piperazine(3 ml) added. The reaction was refluxed for 4 hours and then evaporatedto dryness in vacuo. The residue was partitioned between aqueous ammoniaand ether and the ether phase extracted with N,HCl. The product wasprecipitated by the addition of 0.88 ammonia and extracted into ether,washed with water, dried (MgSO₄) and evaporated in vacuo, m.p. 175-177°C. (EtOAc/hexane).

Similarly prepared was:

(b)2-Ethyl-7-fluoro-10-(1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazpine,m.p. 138°-140° C. (CCl₄ /hexane)

EXAMPLE 26 (a)2-Ethyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine9,10-Dihydro-2-ethyl-4H-thieno[2,3-b][1,5]benzodiazepin-10-one (2.4 g,0.01 mol) was suspended in N-methyl piperazine (10 ml). Titaniumtetrachloride (1.2 ml, 0.011 mol) in dry anisole (5 ml) was added andthe mixture stirred and heated at 120° C. for 2 hours. The reaction waspoured onto ice-water and shaken until a greyish white precipitateformed. The suspension was extracted with methylene chloride until nomore yellow colour was removed. The combined extracts were washed withwater, dried (MgSO₄) and evaporated in vacuo to yield the title compoundas a yellow solid. This solid was triturated with ether, filtered, andrecrystallised from hexane, m.p. 195-197° C.

The free base was then converted to its maleate salt, m.p. 186-188° C.(ethanol/ether).

(b)2-Ethyl-7-fluoro-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

The title compound, m.p. 161°-163° C. (hexane), was prepared using aprocedure similar to that of Example 26(a) from9,10-dihydro-2-ethyl-7-fluoro-4H-thieno[2,3-b][1,5]benzodiazepin-10-one.

Anal. Calc. for C₁₈ H₂₁ FN₄ S C; 62.76; H: 6.14; N: 16.26; F: 5.51; S:9.30% Found C: 62.99; H: 5.87; N: 16.06; F: 5.67; S: 9.32%

The free base was converted to its maleate salt, m.p. 125-127° C.(ethanol-ether).

Anal. Calcd. for C₂₂ H₂₅ FN₄ O₄ S C: 57.37; H: 5.47; N: 12.16; F: 4.12;S: 6.96% Found: C: 57.53; H: 5.54; N: 11.99; F: 4.16; S: 6.93%

The following benzodiazepines were similarly prepared using the processof Example 26(a). The material given beneath the title is the amideintermediate, the melting point is that of the title product and therecrystallisation solvent is indicated in parentheses.

(c)2-Ethyl-6-fluoro-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

9,10-Dihydro-2-ethyl-6-fluoro-4H-thieno[2,3-b][1,5]benzodiazepin-10-one,m.p. 206°-208° C. (hexane); maleate salt, m.p. 125°-127° C. (EtOH/Et₂O).

(d)6,8-Difluoro-2-ethyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

6,8-Difluoro-9,10-dihydro-2-ethyl-4H-thieno[2,3-b][1,5]benzodiazepin-10-one,m.p. 243°-246° C. (CCl₄ /hexane); maleate salt, m.p. 122°-4° C.(EtOH/Et₂ O).

(e)7-Chloro-2-ethyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

7-Chloro-9,10-dihydro-2-ethyl-4H-thieno[2,3-b][1,5]benzodiazepin-10-one,m.p. 235°-240° C., maleate salt, m.p. 119°-121° C. (EtOH/Et₂ O).

(f)2-Ethyl-6-methyl-10-(4-methyl-1-piperazinyl)-6H-thieno[2,3-b][1,5]benzodiazepine

The title compound was similarly prepared using9,10-dihydro-2-ethyl-6-methyl-4H-thieno[2,3-b][1,5]benzodiazepin-10-one,m.p. 177-179° C. (CH₂ Cl₂ /hexane).

(g)7-N,N-Dimethylsulphonamido-2-ethyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

9,10-Dihydro-7-N,N-dimethylsulphonamido-2-ethyl-4H-thieno[2,3-b][1,5]benzodiazepin-10-one,m.p. 225-227° C. (EtOAc/hexane).

(h)7-Fluoro-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

9,10-Dihydro-7-fluoro-4H-thieno[2,3-b][1,5]benzodiazepin-10-one, m.p.228°-230° C. (CH₂ Cl₂ /hexane).

(i)9-Fluoro-12-(4-methyl-1-piperazinyl)-6H-1,2,3,4-tetrahydrobenzothieno-[2,3-b][1,5]benzodiazepine

9-Fluoro-6H-1,2,3,4,11,12-hexahydrobenzothieno[2,3-b][1,5]benzodiazepin-12-one,m.p. 196-199° C. (CH₂ Cl₂ hexane).

(j)7-Fluoro-2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

7-Fluoro-2-methyl-9,10-dihydro-4H-thieno[2,3-b][1,5]benzodiazepin-10-one,m.p. 160-165° C. (dec.) (EtOAc/hexane).

(k)7-Fluoro-2-phenyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b]1,5]benzodiazepine,dihydrochloride

The free base of the chloride identified above was prepared using7-fluoro-2-methyl-9,10-dihydro-4H-thieno[2,3-b][1,5]benzodiazepin-10-one.This was then converted to the dihydrochloride, m.p. 235-240° C. (dec.)(MeOH/hexane).

(l)7-Trifluoromethyl-2-ethyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

7-Trifluoromethyl-2-ethyl-9,10-dihydro-4H-thieno[2,3-b][1,5]benzodiazepin-10-one.

(m) 10-(4-Methyl-1-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepine

9,10-Dihydro-4H-thieno[3,2-b][1,5]benzodiazepin-10-one, m.p. 202-206° c.(CCl₄).

(n)7-Fluoro-10-(4-methyl-1-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepine

7-Fluoro-9,10-dihydro-4H-thieno[3,2-b][1,5]benzodiazepin-10-one, m.p.206-208° C.

(o)7-Chloro-10-(4-methyl-1-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepine

7-Chloro-9,10-dihydro-4H-thieno[3,2-b][1,5]benzodiazepin-10-one, m.p.225°-226° C. (CHCl₃).

(p)7-Chloro-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

7-Chloro-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepine

7-Chloro-9,10-dihydro-4H-thieno[3,4-b[1,5]benzodiazpin-10-one, m.p.169°-170° C.

(q)7-Methylthio-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine(r)10-(4-Methyl-1-piperazinyl)-7-trifluoromethyl-4H-thieno[3,4-b][1,5]benzodiazepine

6-Trifluoromethyl-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one,m.p. 202° c. (CCl₄ /petrol 40°-60° C.).

(s)3-Chloro-10-(4-methyl-1-piperazinyl)-4H-thieno]3,4-b][1,5]benzodiazepine

3-Chloro-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one.

(t) 10-(4-Methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine m.p.220-201° C.

(u)7-Fluoro-10-(4-methyl-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepinem.p. 190.5 - 191.5° C.

(v)6,7-Dichloro-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepinem.p. 200-202° C.

(w)2-i-Propyl-7-fluoro-10-(4-methyl-1-piperazinyl)-4H-thiene[2,3-b][1,5]benzodiazepine

(x)2-n-Hexyl-7-fluoro-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

(y)1-Methyl-7-fluoro-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

(z)1-Methyl-2-ethyl-7-fluoro-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

(aa)6,7-Difluoro-2-ethyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine,m.p. 172° C. (CCl₄ /hexane).

(bb)7-Fluoro-10-(4-methyl-1-piperazinyl)-1-ethyl-4H-thieno[3,4-b][1,5]benzodiazepine

(cc)2-Ethyl-7-fluoro-10-(4-methyl-1-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepine

EXAMPLE 27

The processes of Example 26 could be repeated by using the thioamidesproduced by the process of Example 24 in place of the amides, withproduction of the benzodiazepines specified in Examples 26(a) to (cc).

EXAMPLE 2810-(4-Methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

4H-2,5-Dihydrothieno[3,4-b][1,5]benzodiazepin-10-one (10 g) in dryanisole (5 ml) was heated with stirring in the presence of titaniumtetrachloride (0.04 ml) and N-methylpiperazine to 120° C. The reactionwas quenched after 11/2 hours, shaken with ethyl acetate, which was runoff, evaporated to dryness at 70° C. under reduced pressure. The solidwas column chromatographed down a "Florisil", 5% methanol in chloroform,column. The collected fractions, when evaporated to dryness, yielded thetitle compound as a yellow solid, m.p. 200°-201° C.

EXAMPLE 2910-(4-Methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

10-Amino-4H-2,5-dihydro-thieno[3,4-b][1,5]benzodiazepine (2.17 g) inanisole, and N-methylpiperazine (10 ml) were stirred at room temperaturein a 100 ml. round-bottomed flask. The complex derived from titaniumtetrachloride (2.6 ml) in anisole (15 ml) was added slowly to thestirred mixture. After complete addition, the reaction mixture wasstirred under nitrogen and heated to 120° C. The reaction was followedby t.l.c. which witnessed formation of the aromatised starting materialbefore condensation with the N-methylpiperazine. The mixture was heatedovernight at 120° C., cooled, and poured into water. The aqueous mixturewas made basic with dilute sodium hydroxide solution, and shaken withchloroform. The organic extract was washed with water, dried andevaporated to an oil under vacuum. Column chromatography of the oil on asilicic acid column with 5% methanol in chloroform gave fractionscontaining the title compound

EXAMPLE 3010-(4-Methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

10-Amino-4H-thieno[3,4-b][1,5]benzodiazepine (215 mg) in anisole (1 ml)was treated with N-methylpiperazine (2.5 ml) at room temperature undernitrogen. Titanium tetrachloride (0.12 ml) in anisole (1 ml) was addedto the stirred mixture at room temperature. The mixture, under nitrogen,was heated to 110° C. and stirred overnight.

The resulting mixture was cooled, poured into water, made basic withdilute sodium hydroxide solution, and shaken with chloroform. Theorganic solvent was extracted, washed with water, dried and evaporatedto an oil under vacuum. The required product was isolated via columnchromatography using a silicic acid column with 5% methanol inchloroform to give the title product as a pale yellow solid, m.p.200°-201° C.

Similarly, the benzodiazepines specified in Examples 26(a) to (cc) wereprepared from the corresponding 10-amino derivatives, although in manycases yields were extremely poor.

EXAMPLE 31

(a)10-(4-Carboethoxy-1-piperazinyl)-2-ethyl-7-fluoro-4H-thieno[2,3-b][1,5]benzodiazepine

A suspension of9,10-dihydro-2-ethyl-7-fluoro-4H-thieno[2,3-b][1,5]benzodiazepin-10-one(2.6 g, 0.01 mol) in a mixture of anisole (5 ml), toluene (10 ml) andethyl-N-piperazino-carboxylate (9.6 g, 0.06 mol) was treated with asolution of titanium tetrachloride (1.2 ml, 0.011 mol) in dry anisole (5ml) and toluene (10 ml). The mixture was refluxed for 3 hours and pouredinto ice-water (200 ml). The aqueous material was extracted withmethylene chloride, washed with water, dried (MgSO₄) and evaporated to agum (5 g). Trituration with ether gave the title product as a yellowsolid, m.p. 168°-171° C. (CH₂ Cl₂ /hexane); maleate salt, m.p. 149°-151°C. (EtOH/Et₂ O).

Similarly prepared were:

(b)10-(4-Carboethoxy-1-piperazinyl)-2-ethyl-4H-thieno[2,3-b][1,5]benzodiazepine

m.p. 169° C. (CH₂ Cl₂ /CCl₄ /hexane).

(c)10-(4-Carboethoxy-1-piperazinyl)-7-chloro-2-ethyl-4H-thiene[2,3-b][1,5]benzodiazepine

m.p. 155-158° C. (EtOAc/hexane).

The title compound was similarly prepared using7-chloro-9,10-dihydro-2-ethyl-4H-thieno[2,3-b][1,5]benzodiazepin-10-one,m.p. 155°-158° C. (EtOAc/hexane).

(d)10-(4-Carboethoxy-1-piperazinyl)-2-ethyl-6-fluoro-4H-thieno[2,3-b][1,5]benzodiazepine

m.p. 176-178° C. (EtOAc/hexane).

(e) 10-(4-Carboethoxy-1-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepinem.p. 166° C. (CHCl₃).

(f)10-(4-Carboethoxy-1-piperazinyl)-7-fluoro-4H-thieno[3,2-b][1,5]benzodiazepinem.p. 162°-164° C. (EtOAc).

(g)10-(4-Carboethoxy-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepinem.p.186-187° C.

(h)10-(4-Carboethoxy-1-piperazinyl)-7-fluoro-4H-thieno[3,4-b][[1,5]benzodiazapinem.p. 197°-199° C.

(i)10-(4-Carboxyethyl-1-piperazinyl)-6,7-dichloro-4H-thieno[3,4-b][1,5]benzodiazepinem.p. 213°-214° C.

(j)10-(4-Carboxyethyl-1-piperazinyl)-7-chloro-4H-thieno[3,4-b][1,5]benzodiazepine.m.p. 195°-196° C.

EXAMPLE 32 (a)2-Ethyl-7-fluoro-10-(1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

10-(4-carboethoxy-1-piperazinyl)-2-ethyl-7-fluoro-4H-thieno[2,3-b][1,5]benzodiazepine(1.0 g), and potassium hydroxide pellets (6.0 g) in 96% ethanol (50 ml)were refluxed for 16 hours. The resulting suspension was evaporated todryness and partitioned between water and chloroform. The chloroformlayer was washed with water, dried (MgSO₄) and evaporated to give thetitle product as a yellow solid, m.p. 138°-140° C. (CCl₄ /hexane).

The following benzodiazepines were similarly prepared:

(b) 2-Ethyl-10-(1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine m.p.170°-171° C. (EtOAc/hexane).

(c)7-Chloro-2-ethyl-10-(1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepinem.p. 167-169° C.

(d) 10-(1-Piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepine m.p.203°-206° C. (EtOAc).

(e) 7-Fluoro-10-(1-piperazinyl)-4H-thiene[3,2-b][1,5]benzodiazepine m.p.165°-167° C. (CCl₄)

(f) 10-(1-Piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine m.p.233°-235° C.

(g) 7-Fluoro-10-(1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine m.p.192°-193° C.

(h) 6,7-Dichloro-10-(1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepinem.p. 213°-214° C.

(i) 7-Chloro-10-(1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine m.p.178°-179° C.

EXAMPLE 33

(a)10-(4-p-Chlorobenzyl-1-piperazinyl)-2-ethyl-7-fluoro-4H-thieno[2,3-b][1,5]benzodiazepine

2-Ethyl-7-fluoro-10-(1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine(1.0 g, 0.003 mol), p-chlorobenzyl chloride (0.38 ml, 0.0033 mol) andtriethylamine (1.0 ml) in 90% ethanol (25 ml) was refluxed for 16 hours.The reaction mixture was evaporated to dryness and partitioned betweenwater and methylene chloride. The organic extracts were washed withwater, dried (MgSO₄) and evaporated in vacuo to yield the title productas a solid, melting point 166°-168° C. when recrystallised from CH₂ Cl₂/hexane.

The following compounds were similarly prepared:

(b)10-(4-Benzyl-1-piperazinyl)-2-ethyl-4H-thieno[2,3-b][1,5]benzodiazepinem.p. 79-80° C.

However, in this reaction benzyl bromide was as the alkylating agent.

(c) 10-(4'-Benzyl-1'-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepinem.p. 198°-200° C. (EtOAc).

(d)7-Fluoro-10-(4'-benzyl-1'-piperazinyl)-4H-thieno[3,2-b][1,5]benzodiazepinem.p. 180°-182° C. (CHCl₃).

(e) 10-(4-Benzyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine m.p.221°-222.5° C.

(f)2-Ethyl-7-fluoro-10-(4-cyclopropyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

EXAMPLE 34 (a)2-Ethyl-7-fluoro-10-[4-(2-hydroxyethyl)-1-piperazinyl]-4H-thieno[2,3-b][1,5]benzodiazepine

2-Ethyl-7-fluoro-10-(1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine(1.65 g, 0.005 mol) and ethylene bromohydrin (1.25 g, 0.01 mol) in 90%ethanol (150 ml) and triethylamine (2.02 g, 0.02 mol) were refluxedunder a nitrogen atmosphere for 16 hours. The reaction mixture wasevaporated to dryness, partitioned between water and methylene chloride,the methylene chloride extract washed with water, dried (MgSO₄) andevaporated to dryness to yield the title compound as a solid, m.p.173°-175° C. (CH₂ Cl₂ /hexane).

Similarly prepared were:

(b)7-Fluoro-10-[4-(2-hydroxyethyl)-1-piperazinyl]-4H-thieno[3,2-b][1,5]benzodiazepinem.p. 205°-210° C. (CHCl₃).

(c)2-Ethyl-7-fluoro-10-[4-(3-hydroxypropyl)-1-piperazinyl]-4H-thieno[2,3-b][1,5]benzodiazepinem.p. 145°-148° C. (CH₂ Cl₂ /hexane).

(d)2-Ethyl-10-[4-(2-hydroxyethyl)-1-piperazinyl]-4H-thieno[2,3-b][1,5]benzodiazepinem.p. 175-176° C. (EtOAc/hexane).

(e)10-[4-(3-Hydroxypropyl)-1-piperazinyl]-4H-thieno[3,2-b][1,5]benzodiazepinem.p. 172-173° C. (EtOAc/hexane).

(f)7-Fluoro-10-[4'-(3-hydroxypropyl)-1'-piperazinyl]-4H-thieno[3,2-b][1,5]benzodiazepinem.p. 138°-140° C. (CHCl₃).

(g)10-[4-(3-hydroxypropyl)-1-piperazinyl]-4H-thieno[3,4-b][1,5]benzodiazepinem.p. 184° C.

EXAMPLE 35 (a)2-Ethyl-7-fluoro-10-[3-N[4-methyl-1-piperazinyl]propylamino]-4H-thieno[2,3-b][1,5]benzodiazepine

9,10-Dihydro-2-ethyl-7-fluoro-4H-thieno[2,3-b][1,5]benzodiazepin-10-thione(2 g, 0.0072 mol), 1-(3-aminopropyl)-4-phenylpiperazine (1.3 ml),triethylamine (8 ml), and dry dimethylformamide (10 ml) were heatedunder nitrogen at 65° C. until the reaction was complete by t.l.c. (Et₂O) (20 hours). The mixture was poured onto excess molar maleic acidsolution, washed twice with ether and basified with 0.88 ammoniasolution, extracting with ethylacetate. The combined extracts werewashed with water, dried (MgSO₄) and the solvent evaporated to give thetitle product as a yellow semi solid which was crystallised from ethylacetate/n-hexane, m.p. 181° C.

The following compounds were similarly prepared:

(b)10-(3-N,N-Dimethylaminopropylamino)-2-ethyl-7-fluoro-4H-thieno[2,3-b][1,5]benzodiazepine dimaleate m.p. 193°-195° C. (isopropanol/n-hexane).

(c)2-Ethyl-7-fluoro-10-(3-N-morpholinopropylamino)-4H-thieno[2,3-b][1,5]benzodiazepinedimaleate m.p. 182°-186° C. (isopropanol/n-hexane).

(d)2-Ethyl-7-fluoro-10-(2-hydroxyethylamino)-4H-thieno[2,3-b][1,5]benzodiazepinemaleate m.p. 196°-198° C. (ethanol/ethyl acetate/n-hexane).

(e)10-(2-N,N-Dimethylaminoethylamino)-2-ethyl-7-fluoro-4H-thieno[2,3-b][1,5]benzodiazepinemaleate m.p. 183°-184° C. (ethanol/ethyl acetate/n-hexane).

(f)2-Ethyl-7-fluoro-10-(3-hydroxypropylamino)-4H-thieno[2,3-b][1,5]benzodiazepinemaleate m.p. 174°-175° C. (ethanol/ethyl acetate/n-hexane).

(g)2-Ethyl-7-fluoro-10-(2-N-piperidinoethylamino)-4H-thieno[2,3-b][1,5]benzodiazepinesesquifumarate m.p. 184°-185° C. (ethanol/ethyl acetate/n-hexane).

(h)2-Ethyl-7-fluoro-10-(2-N-morpholinoethylamino)-4H-thieno[2,3-b][1,5]benzodiazepinefumarate m.p. 189°-203° C. (ethanol/ethyl acetate/n-hexane).

(i)2-Ethyl-7-fluoro-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepinem.p. 153°-155° C. (ethylacetate/n-hexane).

(j)2-Ethyl-7-fluoro-10-(4-phenyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepinem.p. 154°-156° C. (CH₂ Cl₂ /hexane).

(k)10-(4-Benzyl-1-piperazinyl)-2-ethyl-7-fluoro-4H-thieno[2,3-b][1,5]benzodiazepinem.p. (di HCl salt) 265°-270° C. (EtOH/Et₂ O).

(l)10-[4-(m-Chlorophenyl)-1-piperazinyl]-2-ethyl-7-fluoro-4H-thieno[2,3-b][1,5]benzodiazepine hydrochloride m.p. (HCl salt) 250°-260° C.

(m)2-Ethyl-7-fluoro-10[4-(m-trifluoromethylphenyl)-1-piperazinyl]-4H-thieno[2,3-b][1,5]benzodiazepinehydrochloride m.p. (HCl salt) 184°-187° C.

(n) 10-(2-N-piperidinoethylamino)-4H-thieno[3,4-b][1,5]benzodiazepinem.p. 182°-183° C.

EXAMPLE 36

(a)10-[4-(3-Decanoyloxypropyl)-1-piperazinyl]-4H-thieno[3,2-b][1,5benzodiazepinehydrochloride

To a solution of10-[4-(3-hydroxypropyl)-1-piperazinyl]-4H-thieno[3,2-b][1,5]benzodiazepine(1.71 g, 0.005 mol) in dry benzene (40 ml) was added decanoyl chloride(1.42 g, 0.0075 mol) in benzene (10 ml) dropwise with stirring and thesolution heated at 75° C. until the reaction had gone to completion byTLC. The reaction mixture on washing gave the title compound.

Similarly, using the process of Example 36(a) other hydroxyalkylderivatives of Example 34 were esterified to give the correspondingdecanoate and ananthate esters.

The following Examples illustrate pharmaceutical formulations containingthe active compounds of the invention. The active ingredient used was2-ethyl-7-fluoro-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine;however, it will be appreciated that this compound may be replaced byother active solid compounds of the invention.

EXAMPLE 37

Tablets each containing 10 mg of active ingredient were made up asfollows:

    ______________________________________                                        Active ingredient      10      mg                                             Potato Starch          45      mg                                             Lactose                35      mg                                             Polyvinylpyrrolidone   4       mg                                             (as 10% solution in                                                           water)                                                                        Sodium starch glycolate                                                                              4.5     mg                                             Magnesium Stearate     0.5     mg                                             Talc                   1       mg                                             Total                  100     mg                                             ______________________________________                                    

The active ingredient, starch and lactose were passed through a No. 44mesh B.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone was mixed with the resultant powders which werethen passed through a No. 12 mesh B.S. sieve. The granules so producedwere dried at 50°-60° C. and passed through a No. 16 mesh B.S. sieve.The sodium starch glycolate, magnesium stearate and talc, previouslypassed through a No. 60 mesh B.S. sieve, were then added to the granuleswhich, after mixing, were compressed on a tablet machine to yieldtablets each weighing 100 mg.

EXAMPLE 38

Capsules each containing 20 mg of medicament were made as follows:

    ______________________________________                                        Active ingredient     20      mg                                              Starch                89      mg                                              Lactose               89      mg                                              Magnesium Stearate    2       mg                                              Total                 200     mg                                              ______________________________________                                    

The active ingredient, lactose, starch and magnesium stearate werepassed through a No. 44 mesh B.S. sieve and filled into hard gelatincapsules in 200 mg quantities.

EXAMPLE 39

Suppositories each containing 25 mg. of active ingredient were made asfollows:

    ______________________________________                                        Medicament          25         mg                                             Saturated fatty acid                                                          glycerides to       2,000      mg                                             ______________________________________                                    

The active ingredient was passed through a No. 60 mesh B.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture was then poured into asuppository mould of nominal 2 g capacity and allowed to cool.

EXAMPLE 40

Suspensions each containing 5 mg of medicament per 5 ml dose were madeas follows:

    ______________________________________                                        Medicament            5       mg                                              Sodium carboxymethyl-                                                         cellulose 50          50      mg                                              Syrup                 1.25    ml                                              Benzoic Acid solution 0.10    ml                                              Flavour                       q.s.                                            Colour                        q.s.                                            Chloroform water to   5       ml                                              ______________________________________                                    

The medicament was passed through a No. 44 mesh B.S. sieve and mixedwith the sodium carboxymethylcellulose 50 and syrup to form a smoothpaste. The benzoic acid solution, flavour and colour were diluted withsome of the chloroform water and added, with constant stirring.Sufficient chloroform water was then added to produce the requiredvolume.

We claim:
 1. A thieno[2,3-b][1,5]benzodiazepine compound of the formula ##STR31## or a pharmaceutically acceptable acid addition salt thereof, wherein R¹ and R² independently represent hydrogen, C₁₋₄ alkyl, halogen, C₁₋₄ haloakyl, nitro, amino, C₁₋₄ alkoxy, C₁₋₄ alkylthio or a group of the formula --SO₂ N(R⁴)₂ where R⁴ is C₁₋₄ alkyl; wherein R⁶ is hydrogen, phenyl, halophenyl, C₁₋₄ alkyl, C₁₋₄ carbalkoxy or --(CH₂)_(n) OH where n is 2 or 3; and wherein the thiophene ring is unsubstituted or is substituted by a C₁₋₄ alkyl group in the 2-position.
 2. The compound of claim 1 which is 2-ethyl-7-fluoro-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine.
 3. The compound of claim 1 which is 2-ethyl-7-chloro-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine.
 4. The compound of claim 1 which is 2-ethyl-7-trifluoromethyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine.
 5. The compound of claim 1 which is 2-ethyl-7-fluoro-10-(1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine.
 6. The compound of claim 1 which is 2-methyl-7-fluoro-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine.
 7. The compound of claim 1 which is 2-isopropyl-7-fluoro-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine.
 8. A method of treating an animal suffering from, or susceptible to, disorder of the CNS, which comprises administering to the animal a chemotherapeutically effective amount of a thieno[2,3-b][1,5]benzodiazepine compound of the formula: ##STR32## or a pharmaceutically-acceptable salt thereof, wherein R¹ and R² independently represent hydrogen, C₁₋₄ alkyl, halogen, C₁₋₄ haloalkyl, nitro, amino, C₁₋₄ alkoxy, C₁₋₄ akylthio or a group of the formula --SO₂ N(R⁴)₂ where R⁴ is C₁₋₄ alkyl; wherein R⁶ is hydrogen, phenyl, halophenyl, C₁₋₄ alkyl, C₁₋₄ carbalkoxy or --(CH₂)_(n) OH where n is 2 or 3; and wherein the thiophene ring is unsubstituted or is substituted by a C₁₋₄ alkyl group in the 2-position.
 9. The method of claim 8 wherein the thieno[2,3-b][1,5]benzodiazepine is 2-ethyl-7-fluoro-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine.
 10. The method of claim 8 wherein the thieno[2,3-b][1,5]benzodiazepine is 2-ethyl-7-chloro-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine.
 11. The method of claim 8 wherein the thieno[2,3-b][1,5]benzodiazepine is 2-ethyl-7-trifluoromethyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine.
 12. The method of claim 8 wherein the thieno[2,3-b][1,5]benzodiazepine is 2-ethyl-7-fluoro-10-(1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine.
 13. The method of claim 8 wherein the thieno[2,3-b][1,5]benzodiazepine is 2-methyl-7-fluoro-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine.
 14. The method of claim 8 wherein the thieno[2,3-b][1,5]benzodiazepine is 2-isopropyl-7-fluoro-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine.
 15. A pharmaceutical formulation comprising as an active ingredient a chemotherapeutically effective amount of a thieno[2,3-b][1,5]benzodiazepine compound of the formula: ##STR33## or a pharmaceutically-acceptable salt thereof, wherein R¹ and R² independently represent hydrogen, C₁₋₄ alkyl, halogen, C₁₋₄ haloalkyl, nitro, amino, C₁₋₄ alkoxy, C₁₋₄ alkylthio or a group of the formula --SO₂ H(R⁴)₂ where R⁴ is C₁₋₄ alkyl; wherein R⁶ is hydrogen, phenyl, halophenyl, C₁₋₄ alkyl, C₁₋₄ l carbalkoxy or --(CH₂)_(n) OH where n is 2 or 3; and wherein the thiophene ring is unsubstituted or is substituted by a C₁₋₄ alkyl group in the 2-position.
 16. The formulation of claim 15 wherein the thieno[2,3-b]-[1,5]benzodiazepine is 2-ethyl-7fluoro-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine.
 17. The formulation of claim 15 wherein the thieno[2,3-b][1,5]benzodiazepine is 2-ethyl-7-chloro-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine.
 18. The formulation of claim 15 wherein the thieno[2,3-b][1,5]benzodiazepine is 2-ethyl-7-trifluoromethyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine.
 19. The formulation of claim 15 wherein the thieno[2,3-b][1,5]benzodiazepine is 2-ethyl-7-fluoro-10-(1-piperazinyl)-4H-thieno[2,3-b][1,5benzodiazepine.
 20. The formulation of claim 15 wherein the thieno[2,3-b][1,5benzodiazepine is 2-methyl-7fluoro-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b[]1,5]benzodiazepine.
 21. The formulation of claim 15 wherein the thieno[2,3-b][1,5]benzodiazepine is 2-isopropyl-7-fluoro-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine. 